N,n&#39;-bisnitrophenoxybenzal-bridged-diamines

ABSTRACT

Alkylenediamine derivatives substituted on each nitrogen atom by 4-(4&#39;&#39;-nitrophenoxy)benzyl or 4-(4&#39;&#39;-aminophenoxy)benzyl, optionally substituted additionally on each nitrogen by lower alkyl, phenylcarbamyl or dihaloacetyl and optionally interrupted in alkylene by cycloalkylene, phenylene, alkylated-phenylene, pyridylene, furylene and thiazolylene. The compounds, which have antibacterial activity, are prepared stepwise by reacting an alkylenediamine with two molar equivalents of 4-(4&#39;&#39;-nitrophenoxy) benzaldehyde and reducing the resulting bis(benzal) alkanediamines.

United States tent 11 1 1111 3,876,701 Surrey Apr. 8, 1975 [5N,N'-BISNITROPHENOXYBENZAL- 3,567,718 3/1971 Elslager ..260/566FXRelated US. Application Data Division of Ser. No. 29,643, April 17,I970, Pat. No. 3,772,370, Continuation-in-part of Ser. No. 652,013, July10, I967. abandoned, which is a continuation of Ser. No. 390,451, Aug.18, I964, abandoned.

Inventor:

us. c1. 260/566 r 1m. (:1. C07c 119/00 Field of Search 260/566 FReferences Cited UNITED STATES PATENTS 7/1957 Shepard et al. 2601566 F XPrimary E.\'aminerLeon Zitver Assistant Examiner-Gerald A. SchwartzAttorney, Agent, or FirmRobert K. Bair; Theodore C. Miller; B. WoodrowWyatt [57] ABSTRACT Alkylenediamine derivatives substituted on eachnitrogen atom by 4-(4'-nitrophenoxy)benzy] or 4-(4'-aminophenoxy)benzyl,optionally substituted additionally on each nitrogen by lower -alkyl,phenylcarbamyl or dihaloacetyl and optionally interrupted in alkylene bycycloalkylene, phenylene, alkylatedphenylene, pyridylene, furylene andthiazolylene. The compounds, which have antibacterial activity, areprepared stepwise by reacting an alkylenediamine with two molarequivalents of 4-(4'-nitrophenoxy)benzaldehyde and reducing theresulting bis(benzal)alkanediamines.

7 Claims, No Drawings N,N '-BISNITROPHENOXYBENZAL-BRIDGED- DIAMINES Thisapplication is a division of my copending appli- This invention relatesto alkanediamine derivatives.

The invention resides in the concept of an alkanediamine substituted oneach nitrogen by 4-(4-nitrophenoxy)-benzyl or 4-(4'-aminophenoxy)benzyland optionally substituted additionally on each nitrogen by lower-alkyl,phenylcarbamyl or dihaloacetyl.

2 trated by methyl, ethyl, n-propyl, isopropyl, 2-butyl, nhexyl, and thelike.

The term dihaloacetyl, as used herein, e.g., for R in Formula I, meansacetyl radicals disubstituted by any halogen which can be the same ordifferent for a given' radical, and are illustrated by dichloroacetyl,difluoroacetyl, dibromoacetyl, diiodoacetyl, bromochloroacetyl,

'chlorofluoroacetyl, and the like.

As used in Formula I and elsewhere herein the alkylene radical Y whenuninterrupted has from two to ten carbon atoms and has its connectinglinkages on different carbon atoms, as illustrated by -CH Cl-l CH(CH )CHCH CHCH C(C l-l CH -CH CH CH CH Cl-lCH CI-l CH CH CH CH CI-l Cl-l CHCH(CH -(Cl-l (CH )hd 7, (CH and the like; and, when interrupted, isillustrated by -CH CH OCH CH -CH CH OCH CH CH Illustrative and preferredembodiments of my com- CH CH SCH CH CH CH CH SCH CH C- pounds are thoseof Formula I H -CH CH NHCH CH j R R z. o-

-cn -I't-Y-1':-ci -0- -z where Z is nitro or amino, R is hydrogen,lower-alkyl, CH CH CH NHCH CH CH phenylcarbamyl or dihaloacetyl, and Yis alkylene having from two to ten carbon atoms and having its con-CH2CH(CH3)NHCH(CH3)CH2 necting linkages on different carbon atoms. Thealkyl- CH(CH )CH NHCH CH(CH ene moiety can be interrupted by O, S, NH,N(lower- -CH(CH )CH NHCH(CH )Cl-l alkyl), cycloalkylene having fromthree to six ring carbon atoms, phenylene, phenylene having from one tobly from one to six carbon atoms which can be arranged as straight orbranched chains, and are illus- -CH CH g-6150K 0 and the like.

The two connecting linkages of each interrupting cycloalkylene,phenylene, pyridylene, furylene and thiazolylene moiety can be attachedto any pair of available carbon atoms of said ring moiety.

The compounds of Formula l where R is hydrogen and Z is nitro (FormulaIA) are prepared as follows:

III

The intermediate N,N-bis[4-(4'-nitrophenoxy)benzal- ]alkanediamines ofFormula IV also constitute another aspect of my invention; thesecompounds are not only useful as intermediates in the preparation of thecompounds of Formula IA but also have antibacterial activity as notedhereinbelow. The intermediate diamines of Formula III are generallyknown compounds which are prepared by generally known methods e.g., bythe reductive amination of the corresponding bis-oxoalkyl compound, theamination of the bis-haloalkyl compound or the reduction of thebis-nitrile, bis-oxime, bisazide, or analogous other bis-higher-valencynitrogen compound. The diamine intermediates in some cases are alsoconveniently prepared from unsymmetrical starting niaterials as will beapparent to those skilled in the art of organic chemistry.

The compounds of Formula I where Z is N and R is lower-alkyl,phenylcarbamyl or dihaloacetyl are prepared from the compounds ofFormula IA by reacting a compound of Formula IA with an alkylatingagent, phenylisocyanate or a dihaloacetyl halide respectively.

The compounds of Formula I where Z is Nl-I are prepared by reducing thecorresponding compounds where Z is N0 utilizing reducing agentseffective to reduce nitro to amino.

The above-noted processes are illustrated in the specific exampleshereinbelow.

My compounds of Formula I where Z is amino are useful in the free baseform or in the form of their acidaddition salts, and both forms arewithin the purview of the invention, and, in fact, are considered to beone and the same invention. The acid addition salts are simply a moreconvenient form for use; and, in practice, use of the salt forminherently amounts to use of the base form. The acids which can be usedto prepare the acid addition salts are preferably those which produce,

when combined with the free base, chemotheraproperties inherent in thecations. In practicing my invention, I found it convenient to employ thehydrochloride salt. However, other appropriate chemotherapeuticallyacceptable salts within the scope of the invention are those derivedfrom mineral acids such as hydrobromic acid, hydriodic acid, nitricacid, phos- 65 phoric acid, sulfamic acid, and sulfuric acid; andorganic acids such as acetic acid, citric acid, tartaric acid,

I tate lactic acid, methanesulfonic acid, ethanesulfonic acid, quinicacid, and the like, giving the hydrobromide, hydriodide, nitrate,phosphate, sulfamate, sulfate, acecitrate, tartarate, lactate,methanesulfonate, ethanesulfonate and quinate, respectively.

The acid-addition salts are prepared preferably by reacting the freebase and acid in an organic solvent, e.g., ethanol, in which case thesalt separates directly or can be obtained by concentration of thesolution.

Although chemotherapeutically acceptable salts are preferred, allacid-addition salts are within the scope of my invention. Allacid-addition salts are useful as sources of the free base from even ifthe particular salt per se is not desired as the final product, as forexample when the salt is formed for purposes of purification oridentification, or when it is used as an intermediate in preparing achemotherapeutically acceptable salt by ion exchange procedures.

The molecular structures of the compounds of my invention areestablished by their modes of synthesis and corroborated by thecorrespondence of calculated and found values for the elementaryanalyses.

My compounds of Formulas I and IV have been tested by standardbiological evaluation procedures and found to have antibacterialproperties, e.g., when tested according to standard in vitrobacteriological evaluation procedures. They have been found to possessantibacterial activity, for example, against Staphylococcus aureus,Eberthella typhi, Clostridium welchii, and Pseudomonas aeruginosa, attest concentration levels in the range of about 0.005 mg./cc. to about1.0 mg./cc., as illustrated below in the examples.

Also, some of my compounds of Formula IV have been tested by standardchemotherapeutic evaluation procedures in vivo in hamsters and found topossess amebacidal activity. As illustrated below in the examples, thesecompounds when administered orally to hamsters infected with Endamoebacricetic have been found to clear the animals of the amebic infection atdose levels from about 12.5 to 300 mg./kg./day.

The following examples will further illustrate the invention without,however, limiting it thereto.

EXAMPLE 1 A. N,N'-bis[4-(4-nitrophenoxy)benzal]-1,6- hexanediamine Asolution containing 48.7 g. of 4-(4- nitrophenoxy)benzaldehyde and 1 1.6g. of 1,6- hexanediamine in 250 cc. of benzene was refluxed with acontinuous separator connected to the reaction vessel for removal ofwater formed by the reaction. Although the reaction was complete within2 hours, as shown by nitrophenoxy)benzal]-1 ,6-hexanediamine,

Anal. Calcd. for C H N O C, 67.83; H, 5.34; N, 9.89. Found: C, 67.49; H,5.33; N, 9.71.

N,N'-bis[4-(4'-nitrophenoxy )benzal]-1 ,6- hexanediamine whenadministered orally to hamsters infected with Endamoeba criceti wasfound to clear 4 out of 10, 6 out of 10, and 3 out of 5 of the animalsat respective dose levels of 25, 50 and 100 mg./kg./day. When tested bystandard in vitro bacteriological evaluation procedures,N,N'-bis-[4-(4'- nitrophenoxy)benzall-l ,6-hexanediamine was found tohave bacteriostatic activity against Staphylococcus aureus, Eberthellatyphi, Clostridium welchii and Pseudomonas aeruginosa at respectiveconcentrations of 0.1, 1.0, 0.5 and 1.0 mg./cc.

Following the procedure described in Example 1A using molar equivalentquantities of 4-(4'-nitrophenoxy)benzaldehyde and the appropriatediamine, the following compounds can be prepared:

B. N,N'-bis[4-(4' nitrophenoxy)benzal]-1,4- butanediamine, using1,4-butanediamine.

C. N,N'-bis[4-(4-nitrophenoxy)benzal]-1,10- decanediamine, using1,10-decanediamine.

D. Bis {2-[4-(4 -nitrophenoxy)benzalamino]ethy1} ether, usingbis(2-aminoethyl) ether.

E. Bis{2-[4-(4'-nitrophenoxy)benzalarnino]ethyl} sulfide, usingbis(2-aminoethy1) sulfidel EXAMPLE 2N,N'-bis[4-(4'-nitrophenoxy)benzal]-1,8- octanediamine was preparedfollowing the procedure described in Example 1A using 48.7 g. of 4-(4'-nitrophenoxy)benzaldehyde, 14.4 g. of 1,8- octanediamine, and 250 cc. ofbenzene. There was thus obtained a quantitative yield of the product,N,N'- bis[4-(4'-nitrophenoxy)benzal]- 1 ,8-octanediamine. Afterrecrystallization once from chloroform-npentane and once from isopropylalcohol, it melted at 10l.2103.0C. (corr.).

Anal. Calcd. for C H N O C, 68.68; H, 5.76; N, 9.42. Found: C, 68.91; H,5.87; N, 9.53.

N,N-bis[4-(4'-nitrophenoxy )benzal]-l ,8- octanediamine whenadministered orally to hamsters infected with Endamoeba criceti wasfound to clear 1 1 out of 5, 2 out of 5, and 2 out of 5 of the animalsat respective dose levels of 12.5, 25 and 50 mg./kg./day. When tested bystandard in vitro bacteriological evaluation procedures,N,N'-bis[4-(4'-nitrophenoxy)benzal]-l ,8-octanediamine was found to havebacteriostatic activity against Staphylococcus aureus, Eberthella typhiand Clostridium welchii at respective concentrations of 0.1, 1.0 and0.75 mg./cc.

6 EXAMPLE '3 N,N'-bis[4-(4'-nitrophenoxy)benza1]-1,2- I ethanediaminewas prepared as in Example 1A using 40.3 g. of4-(4'-nitrophenoxy)bennzaldehyde, 4.98 g. of ethylenediamine, 200 cc. ofbenzene, and a reflux period of ninety minutes. The product wasrecrystallized from dioxane to yield 28.5 g. of the product, N,N'-bis[4-(4'-nitrophenoxy)benzal]-l ,2- 10 ethanediamine, m.p. l67.2169.4C.(corr.).

Anal. Calcd. for C H N O C, 65.87; H, 4.35; N, 10.97. Found: C, 65.96;H, 4.27; N, 10.72.

N,N'-bis[4-(4'-nitrophenoxy)benzal]-1,2- ethanediamine when administeredorally to hanisters infected with Endamoeba criceti was found to clear 2out of 5 of the animals at a dose level of 100 mg./kg./day.

EXAMPLE 4 propanediamine was prepared as in Example 1A using 48.6 g. of4-(4'-nitrophenoxy)benzaldehyde, 7.4 g. of 1,3-propanediamine, 200 cc.of benzene, and a reflux period of three hours. After severalrecrystallizations from acetonitrile, there was obtained 10.1 g. ofN,N'-

bis[4-(4-nitrophenoxy)benzal]-l,3-propanediamine,

m.p. 1l9.4-12l.6C. (corr.).

Anal. Calcd. for C H N O C, 66.40; H, 4.61; N, 10.68.

Found: C, 66.71; H, 4.51; N, 10.69.

EXAMPLE 5 Trans-N,N'-bis[4-(4'- nitrophenoxy)benzalaminomethyl]-l,4-cyclohexane was prepared as in Example 1A using 24.3 g. of 4-(4-nitrophenoxy)benzaldehyde, 7.1 g. of transl,4-bis(aminomethyl)cyclohexane, 100 cc. of benzene, and

a reflux period of one hour. There was thus obtained 2.4 g. oftrans-N,N-bis[4-(4'- nitrophenoxy)benzalaminomethyl]-1,4-cyclohexane,m.p. l96.6206.0C. (corr.) after recrystallization from dioxane.

Anal. Calcd. for CMH3ZN4OG: C, 68.91; H, 5.45; N, 9.46. Found: C, 68.65;H, 5.41; N, 9.60.

When tested by standard in vitro bacteriological evaluation procedures,trans-N,N'-bis[4-(4- EXAMPLE 6 A. N,N'-bis[4-(4-nitrophenoxy)benzyl]- l,8- octanediamine To a filtered mixture containing 65.8 g. of N,N-bis[4-(4'-nitrophenoxy)benzal]- l ,8- octanediamine, 1000 cc. ofmethanol, and 150 cc. of dioxane was added in small portions 12.6 g. ofsodium borohydride. The mixture was stirred for an additional ninetyminutes after all of the sodium borohydride had been added. The mixturewas then concentrated to remove the solvents and the concentrate addedto 750 cc. of water. The resulting precipitate was collected,recrystallized from cyclohexane, washed with water and dried to yield51.5 g. of the product, N,N-bis[4-(4- nitrophenoxy)benzyl]-l,8-octanediamine, m.p. 59,66l.0C. (corr.).

Anal. Calcd. for C l-1 N C, 68.20; H, 6.40; N, 9.36. Found: C, 68.47; H,6.15; N, 9.12.

N,N-bis[4-(4-nitrophenoxy)benzyl]-l,8- octanediamine when testedaccording to standard in vitro bacteriological procedures was found tohave antibacterial activity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.0005 0.005Eberthella lyphi 0.0075 0.025 Clastridium welclrii 0.05 0.075Pseudomonas aeruginosa 0.75 1.0

Following the procedure described in Example 6A using molar equivalentquantities of the appropriate N,-N-bis[4-(4-nitrophenoxy)benzal]-diamine and sodium borohydride, thefollowing compounds can be prepared.

B. N,N'-bis[4-(4-nitrophenoxy)benzyl]-l ,3- propanediamine, using N,N-bi[4-(4' nitrophenoxy)benzal]-l ,3-propanediamine.

C. N,N '-bis[4-(4'-nitrophenoxy )benzyl]- l ,4- butanediamine, usingN,N'-bis[4-(4'- nitrophenoxy)benzal]-l ,4-butanediamine.

D. N,N'-bis[4-(4-nitrophenoxy)benzyl]-l ,10- decanediamine, usingN,N'-bis[4-(4'- nitrophenoxy)benzal]-1,10-decanediamine.

E. Bis{2-[4-(4'-nitrophenoxy)benzylamino]ethyl} ether, using bis{2-[4-(4-nitrophenoxy)benzalaminolethyl} ether.

F. Bis{2-[4-(4'-nitrophenoxy)benzylamino1ethyl} sulfide, using bis{2-[4-(4'-nitrophenoxy)berizalamino]ethyl} sulfide.

EXAMPLE 7 N,N'-bis[ 4-(4-nitrophenoxy)benzyl]-l ,6- hexanediamine wasprepared following the procedure described in Example 6A using 63.5 g.of N,N-bis[4- (4'-nitrophenoxy )benzal]-l ,6-hexanediamine, 1000 cc. ofmethanol, 150 cc. of dioxane, 12.6 g. of sodium borohydride. There wasthus obtained 48.5 g. of N,N'- bis[4-(4'-nitrophenoxy)benzyl]-1,6-hexanediamine, m.p. 89.0-9l.2C. (corr.).

Anal. Calcd. for C E- N 0 C, 67.34; H, 6.00; N, 9.82. Found: C, 67.64;H, 5.79; N, 9.64.

N,N-bis[4-(4-nitrophenoxy)benzyl]-l ,6- hexanediamine when testedaccording to standard in vitro bacteriological procedures was found tohave antibacterial activity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal N,N-bis[ 4-(4-nitrophenoxy )benzyl]-l ,2-ethanediamine To a stirred mixture containing 18.5 g. of N,N'-bis[4-( 4-nitrophenoxy)benzal]-l ,2- ethanediamine, 500 cc. of methanol, and 200cc. of dioxane was added in portions over a period of about 15 minutes4.2 g. of sodium borohydride. The mixture was then stirred for anadditional 2 hours, allowed to stand overnight, concentrated in vacuo toremove the solvents and treated with water. The oily layer was extractedwith benzene, the benzene solution dried over anhydrous sodium sulfateand the benzene distilled off to yield an oil which crystallized onstanding. The crystalline material was washed with carbon tetrachlorideand recrystallized twice from propionitrile. There was thus obtained 4.1g. of N,N'-bis[4-(4- nitrophenoxy)benzyl]-l ,Z-ethanediamine, m.p. 119.2-124.8C. (corr.).

Anal. Calcd. for C ,,H N O C, 65.36; H, 5.09; N, 10.89. Found: C, 65.35;H, 5.l3; N, ll.05.

N,N'-bis[4-(4-nitrophenoxy)benzyl]-l ,2- ethanediamine when testedaccording to standard in vitro bacteriological procedures was found tohave antibacterial activity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.0l 0.05 Eberthellatyphi 0.075 0.1 Clostridium welchii 0.0005 0.001 Pseudomonns aeruginosa0.075 0.]

EXAMPLE 9A was stirred for 2 hours. The reaction mixture wasconcentrated, water was added, the aqueous mixture was made basic with35% aqueous sodium hydroxide solution, and the basic mixture wasextracted with tetrahydrofuran. The extracted mixture was concentratedto a semisolid, benzene was added and distilled off, and the remainingsolid was taken up in ether. The ether solution was filtered, thefiltrate concentrated to yield a semi-solid which was dissolved inethanol. To the ethanol solution was added 15 cc. of concentratedhydrochloric acid and the mixture concentrated in vacuo to yield asemi-solid which crystallized on standing. The solid was recrystallizedfrom methanol to yield 6.9 g. of2,2'-dimethylbis{2-[4-(4'-nitrophenoxy)benzylamino] ethyl} amine andl,2'-dimethylbis{2-[4-(4- nitrophenoxy)benzylamino]ethyl} amine(approximately 3:1 mixture of isomers) trihydrochloride mixture, m.p.236.0241.2C. (corr.).

Anal. Calcd. for C l-l N O 3HCl: C, 15.30; N, 10.08. Found: C, 15.28; N,9.91.

2,2'-Dimethylbis{2-[4-(4-nitrophenoxy)benzylamino]ethyl} amine and1,2'-dimethylbis{2-[4-(4'- nitrophenoxy)benzylamino1ethyl} aminetrihydrochloride mixture, when tested according to standard in vitrobacteriological procedures, was found to have antibacterial activity,for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.005 0.025Ebertliella typhi 0.1 0.25 Closlridium welchii 0.001 0.005 Pseudomonasaeruginosa 0.5 1.0 SII'EpIOCOCCllS sp. 0.0075 0.01

EXAMPLE 9B Bis {3-[4-(4'-nitrophenoxy)benzylamino]propyl} amine To astirred mixture of 80.0 g. of bis{3-[4-(4-nitrophenoxy)benzalamino]propyl} amine and 1 l. of methanol was added inportions 13 g. of sodium borohydride. The mixture was stirred for 2hours while the temperature was maintained at 8-l0C., then concentrated.A solution of the residue in benzene was washed with sodium hydroxidesolution, dried over potassium carbonate and concentrated. Treatment ofa solution of the residue in isopropyl alcohol with an excess ofconcentrated hydrochloric acid afforded a precipitate, which, whenwashed with ether and recrystallized from water, gavebis{3-[4-(4'-nitrophenoxy)benzylamino]- propyl} amine trihydrochloride,mp. 278C. (decomposition, uncorr.).

Anal. Calcd. for C H,,-,N =,O.,.3HCl: Cl, 15.30. Found: Cl, 15.08.

10 Bis{3-[4-(4-nitrophenoxy)benzylamino]propyl}amine trihydrochloride,when tested according to standard in vitro bacteriological procedures,was found to have antibacterial activity, for example, as follows:

Minimum Inhibitory Concentration(meg./ml.)

Staphylococcus aurcus 0.05 Pseudomonas aeruginosa 3.1 Escherichia coli0.2 Proteus rulgaris 125 EXAMPLE 10 A. Trans-l,4-bis[4-(4'-nitrophenoxy)benzylaminomethyl]cyclohexane A mixture containing 15.2 g.of trans-N,N-bis[4-(40'-nitrophenoxy)benzalaminomethyl]-1,4-cyclohexane, 2.94 g. of sodiumborohydride, and 300 cc. of ethanol was stirred for 3 hours and allowedto stand overnight. The reaction mixture was filtered and the filtratedistilled to remove the solvent. The remaining solid was suspended in amixture of 300 cc. of dioxane and 500 cc. of methanol, 3 g. of sodiumborohydride added, and the mixturestirred for 4 hours. The resultingsolution was concentrated in vacuo to yield a solid which was washedwith water, collected, dried in vacuo, and recrystallized frombenzene-n-hexane to yield 11.2 g. of the product, trans-1,4-bis[4-(4nitrophenoxy)benzylaminomethyl]cyclohexane, m.p. l27.6-l30.8 C. (corr.).

Anal. Calcd. for C H N O C, 68.43; H, 6.08; N, 9.39. Found: C, 68.77; H,5.91; N, 9.46.

Trans-l ,4-bis[4-( 4'-nitrophenoxy)benzylaminomethyl]cycl0hexane whentested according to standard in vitro bacteriological procedures wasfound to have antibacterial activity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus Eberthella typhi 0.050.075 Closlridium welchii 0.1 0.1 Streptococcus sp. 0.025 0.025

B. l,2-bis[4-(4-nitrophenoxy)benzylaminomethyl]- cyclobutane can beprepared following the procedure described in Example A usingcorresponding molar equivalent quantities of l,2-bis[4-( 4nitrophenoxy)benzalaminomethyl]cyclobutane and sodium borohydride.

EXAMPLE 11 A. N,N'-Dimethyl-N,N-bis[4-(4-nitrophenoxy)benzyl]-l,6-hexanediamine To a solution containing 19 g. ofN,N-bis[4-(4- nitrophenoxy)benzyl}-l,6-hexanediamine in 69 g. of

formic acid was added 53.3 g. of 37% aqueous formaldehyde solution, andthe resulting reaction mixture was refluxed on a steam bath for 12hours. The reaction mixture was concentrated in vacuo to yield asemi-solid which was taken up in methanol; the methanol solution madebasic with 35% aqueous sodium hydroxide solution; the alkaline solutiondiluted with water to a volume of 250 cc. and extracted withtetrahydrofuran. The extract was concentrated in vacuo to yield an oil,the oil was treated with ether and the mixture filtered to removeinsoluble material. The ether solution was concentrated in vacuo toyield an oil which crystallized on cooling. The solid was dissolved in50 cc. of isopropyl alcohol; 5 cc. of concentrated hydrochloric acid wasadded; and the mixture was concentrated in vacuo to yield a solid. Thesolid was first recrystallized by dissolving in 50 cc. of methanol,filtering the solution and diluting the filtrate with about 250 cc. ofethyl acetate; and then it was recrystallized a second time fromdimethylformamide to yield 11.4 g. of N,N'-dimethyl- N,N-bis[ 4-(4'-nitrophenoxy)benzyl]-1,6- hexanediamine as its dihydrochloride,23l.4233.2C. (corr.).

Anal. Calcd. for C H N O JHCI: C, 60.80; H, 6.00;

Found: C, 60.51; H, 5.83;

N,N-Dimethyl-N,N'-bis[4-(4'-nitrophenoxy)benzyl] 1,6-hexanediamine whentested according to standard in vitro bacteriological procedures wasfound to have antibacterial activity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Slaphylococcus aureus 0.005 0.25 Eberlhe/Ialyphi 0.5 0.75 Clostridium welchii 0.25 0.5 Streptococcus sp. 0.0050.005

nitrophenoxy)benzylamino1ethyl} ether and a mixture of formic acid andformaldehyde.

C. Bis{2-[4-(4-nitrophenoxy)benzylmethylamino]ethyl} sulfide, usingbis{2-[4-(4'- nitrophenoxy)benzylamino]ethyl} sulfide and a mixture offormic acid and formaldehyde.

D. Bis {3-[4-(4'-nitrophenoxy)benzylmethylamino]- propyl} methylamine,using bis{3-[4-(4- nitrophenoxy)benzylamino]propyl} amine and a mixtureof at least 3 molar equivalents of each of formic acid and formaldehydeper mole of the amine.

E. Trans- 1 ,4-bis[4-(4nitrophenoxy)benzylmethylaminomethyl]cyclohexane, using transl,4-bis[4-(4-nitrophenoxy)benzylamino]- cyclohexane and a mixture offormic acid and formaldehyde.

F. N,N'-diethyl-N,N-bis[4-(4'-nitrophenoxy)benzyl]-1,8-octanediamine,using N,N'-bis[4-(4- nitrophenoxy)benzyl]-l,8-hexanediamine and ethyliodide as the alkyline agent, preferably in the presence of anacid-acceptor, e.g., sodium carbonate, and using an aqueous ethanolreaction medium.

G. N,N'-di-n-butyl-N,N'-bis[4-(4'-nitrophenoxy)benzyl]-1,6-hexanediamine, using N,N-bis[4-(4-nitrophenoxy)benzyl ]-l ,6-hexanediamine and n-butyl bromide,preferably using sodium carbonate as an acid-acceptor and aqueousethanol as the reaction medium.

H. N,N'-di-n-hexyl-N,N'-bis[4-(4'-nitrophenoxy)benzyl]-l,4-butanediamine, using N,N- bis[4-( 4'-nitrophenoxy)benzyl]- l ,4-butanediamine and n-hexyl iodid'e,preferably in an aqueous ethanol reaction mixture in the presence ofsodium carbonate.

EXAMPLE 12 Anal. Calcd. for C ,,H N O C, 68.36; H, 5.49; N, 10.40.Found: C, 68.33; H, 5.63; N, 10.35.

N,N-bis[4-(4-nitrophenoxy)benzyl]-N,Nbis(phenylcarbamyl)-l,6-hexanediamine when tested according to standardin vitro bacteriological procedures was found to have antibacterialactivity, for example, as follows:

Minimum Efiective Concentration (mg/cc.)

Bacteriostatic Bactericidal Slaphylococcus aureux 0.075 0.075 Eberlhellaryphi 0.075 O.l Clustridium welchii 0.075 0.1 Pseudomonas aeruginosa0.075 0.l

Following the procedure described in Example 12A using molar equivalentquantities of the appropriate N,-N-bis[4-(4-nitrophenoxy)benzyl]-diamine and phenyl isocyanate, thefollowing compounds can be prepared:

B. N,N-bis[4-(4'-nitrophenoxy)benzyl]-N,N'-bis(phenylcarbamyl)-l,8-octanediamine, using N,N'-bis[4-(4-nitrophenoxy)benzyl]- l ,8-octanediamine.

13 C. N,N-bis[4-(4 '-nitrophenoxy)benzyl] N,Nbis(phenylcarbamyl)-l,3-propanediamine, using N,N'-bis[4-(4'-nitrophenoxy)benzyl]-l ,3-propanediamine.

EXAMPLE 13 A. N,N'-bis(dichloroacetyl)-N,N'-bis[4-(4'-nitrophenoxy)benzyl]-1,Z-ethanediamine To a solution containing 1 1.4 g.of N,N-bis[4-(4- nitrophenoxy)benzyl]-1,Z-ethanediamine in 100 cc. ofethylene dichloride cooled to C. was added slowly with stirring asolution of 7.4 g. of dichloroacetyl chloride in 25 cc. of ethylenedichloride. The reaction mixture was kept basic by slow addition ofaqueous sodium hydroxide solution and was stirred for l additional hourat room temperature. The layers were separated, and the ethylenedichloride layer was washed successively with dilute aqueoushydrochloric acid and water, and then concentrated in vacuo to removethe solvent. The remaining material crystallized on standing and wasrecrystallized from ethyl acetate to yield 3.2 g. ofN,N'-bis-(dichloroacetyl)-N,N-bis[4-(4'- nitrophenoxy)benzyl]-l,Z-ethanediamine, m.p. l50.6-l52.6C. (corr.).

Anal. Calcd. for C H Cl N O C, 52.20; H, 3.56;

Found: C, 52.44; H, 3.60;

N,N'-bis(dichloroacetyl)-N,N-bis[4-(4'- nitrophenoxy)benzyl]-l,2-ethanediamine when tested according to standard in vitrobacteriological procedures was found to have antibacterial activity, forexample, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.75 1 .0 EberthellaIyphi 0.75 0.75 Clostridium weIchii 0.75 l.0 Pseudomonas aeruginosa 0.750.75

14 bis[4-(4'-nitrophenoxy)benzyl]-1,6-hexanediamine and diiodoacetylchloride.

G. N,N'-bis(difluoroacetyl)-N,N-bis[4-(4'-nitrophenoxy)benzyl]-l,8-octanediamine, using N,N'-bis[4-(4-nitrophenoxy)benzyl]-1,8-octanediamine and difluoroacetylchloride.

H. N,N'-bis(dichloroacetyl)-trans-1,4-bis-[4-(4'-nitrophenoxy)benzylaminomethyl]cyclohexane, using transl ,4-bis[4-( 4-nitrophenoxy )benzylaminomethyl]cyclohexane and dichloroacetylchloride.

1 N,N-bis(dichloroacetyl)-l,4-bis[4-(4-nitrophenoxy)benzylaminomethyl]benzene, using 1,4-bis[4-(4-nitrophenoxy)benzylaminomethyl]benzene and dichloroacetylchloride.

EXAMPLE 14 A. N,N-bis[4-(4'-aminophenoxy)benzyl]-l ,8- octanediamine Toa stirred suspension of 6.0 g. of N,-N'-bis[4-(4'-nitrophenoxy)benzyl]-1,S-octanediamine in 50 cc. ofmethanol was added 1.9 g. of sodium borohydride and mg. of 10%palladium-on-charcoal. The reaction mixture was stirred for 10 minutes,allowed to stand an additional 15 minutes, and then filtered to removethecatalyst. The filtrate was distilled to remove the solvent and theresulting filtrate was dissolved in tetrahydrofuran. The solution wasfiltered and to the filtrate was added a solution of hydrogen chloridein ether. The resulting precipitate was collected and recrystallizedfrom hot water to yield 4.6 g. of N,N-'-bis[4-(4'-aminophenoxy)benzyl]-1,8-octanediamine in the form of itstetrahydrochloride, m.p. 300C. (corr.).

Anal. Calcd. for C H N O AHCI: C, 59.64; H, 6.77; CI, 20.72.

Found: C, 59.49; H, 6.46; C], 20.71.

N,N'-bis[4-(4-aminophenoxy)benzyl]-1,8- octanediamine when testedaccording to standard in vitro bacteriological procedures was found tohave antibacterial activity, for example, as follows:

Minimum Efiective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.0075 0.025Ebert/1211a typhi 0.05 0.075 Clostridium welchii 0.1 0.1 Pseudomunasaerugt'nosa 0.75 1.0 Streptococcus .rp. 0.025 0.05

E. N,N-bis[4-(4-aminophenoxy)benzyl]-N,N-di-nbutyll ,6-hexanediamine,using N,N -bis[ 4-( 4- nitrophenoxy)benzyl]-N,N '-di-n-butyl-l ,6-hexanediamine.

F. N,N-bis[4-(4'-aminophenoxy)benzyl]-N,N-di-nhexyl-l ,4-butanediamine,using N,N '-bis[4-( 4 nitrophenoxy )benzyl]-N,N '-di-n-hexyll ,4-butanediamine.

bis(phenylcarbamyl)-l,6-hexanediamine, using N,N-

bis[4-(4-nitrophenoxy)benzyl]-N,N'- bis(phenylcarbamyl)-l,6-hexanediamine.

Trans- 1 ,4-bis[ 4-(4 aminophenoxy)benzylaminomethyl]cyclohexane, usingtrans-1 ,4-bis[4-( 4 nitrophenoxy )benzylaminomethyl]cyclohexane.

EXAMPLE A. l,4-Bis{2-[4-(4-nitrophenoxy)benzalamino]ethyl}-2,3,5,6-tetramethylbenzene was preparedfollowing the procedure described in Example 1 using 24.3 g. of 4-(4-nitrophenoxy)benzaldehyde, 11.0 g. of l,4-bis(2-aminoethyl)-2,3,5,6-tetramethylbenzene, 100 ml. of benzene and a refluxperiod of 5 hours. There was thus obtained 33 g. of the product, m.p.l68-170C.

B. l,4-Bis[4-(4'-nitrophenoxy)benzalaminomethyl]- benzene can beprepared as in Example 15A using corresponding molar equivalentquantities of 4-(4'- nitrophenoxy)benzaldehyde and1,4-bis(aminomethyl)benzene.

C. l,4-Bis{2-[4-(4'-nitrophenoxy)benzalamino]ethyl}-benzene can beprepared as in Example 15A using corresponding molar equivalentquantities of 4-(4'- nitrophenoxy)benzaldehyde andl,4-bis(2-aminoethyl)benzene.

EXAMPLE 16 A Bis{2-[4-(4'-nitrophenoxy)benzylamino]ethyl}2,3,5,6-tetramethylbenzene To asuspension containing 33 g. of 1,4- bis {2-[ 4-(4-nitrophenoxy)benzalamino ethyl} 2,3 ,5 ,6- tetramethylbenzene in amixture of 600 ml. of methanol and 400 ml. of dioxane was added withstirring 5.7 g. of sodium borohydride. The resulting mixture was stirredfor 2 hours, allowed to stand over the weekend at room temperature andthen concentrated in vacuo to yield a semisolid material which waswashed with water and made basic with 35% aqueous sodium hydroxidesolution. The alkaline solution was extracted with tetrahydrofuran andthe extract concentrated to a volume of about 100 ml. To the concentratewas added 10 ml. of concentrated hydrochloric acid. The solid thatseparated was boiled with methanol, collected and dried to yield 31.7 g.of bis{2-[4-(4- nitrophenoxy )benzylamino ethyl} -2 ,3 ,5,-tetramethylbenzene as its dihydrochloride, m.p. 262.2-268.6C. (corr.)with decomposition.

Anal. Calcd. for C ,H N O,,.2HCl: Cl, 9.48; N, 7.49. Found: Cl, 9.7l; N,7.61.

Bis{2-[4-(4'- nitrophenoxy )benzylaminolethyl} 2,3 ,5,6-tetramethylbenzene dihydrochloride when tested according to standardin vitro bacteriological procedures was found to have antibacterialactivity, for example, as follows:

Minimum Effective Concentration (mg/cc.)

Bacteriostatic Bactericidal Staphylococcus aureus 0.0075 0.075Ebert/1811a lyphi 0.1 0.75 Closlridium welchii 0.1 0.25 Slreplococcussp. 0.0025 0.025

20 nitrophenoxy)benzalaminomethyl]benzene.

C. l,4-Bis{2-[4-(4'-nitrbphenoxy)benzylamino]ethyl}-benzene, usingl,4-bis{2-[4-(4'-nitrophenoxy)benzalamino]ethyl}-benzene.

EXAMPLE 17 Following the procedure described in Example 1A using molarequivalent quantities of 4-(4'-nitrophenoxy)benzaldehyde and theappropriate diamine, the following compounds can be prepared:

A. l,2-Bis[4-(4-nitrophenoxy)benzalaminomethyl1- cyclopropane, usingl,2-bis(aminomethyl)cyclopropane.

B. l,3-Bis[4-(4'-nitrophenoxy)benzalaminomethyl]- cyclopentane, using1,3-bis(aminomethyl)cyclopentane.

C. 2,6-Bis[4-(4-nitrophenoxy)benzalaminomethyl1- pyridine, using2,6-bis(aminomethyl)pyridine.

D. 2,5-Bis[4-(4-nitrophenoxy)benzalaminomethyl]- pyridine, using2,5-bis(aminomethyl)pyridine.

E. 3,4-Bis[4-(4-nitrophenoxy)benzalaminomethyl]- pyridine, using3,4-bis(aminomethyl)pyridine.

F. 2,5-Bis[4-(4-nitrophenoxy)benzalaminomethyl]- furn, using2,5-bis(aminomethyl)furan.

l,4Bis[4-( 4 nitrophenoxy)benzalaminomethyl12,5-

dimethylbenzene, using l,4-bis(aminomethyl)-2,5- dimethylbenzene.

H. l,3Bis[4-(4'-nitrophenoxy)benzalaminomethyl]- benzene, usingl,3-bis(aminomethyl)benzene. l.2,4-Bis{2-[4-(4-nitrophenoxy)benzalamino]ethyl} thiazole, using 2,4-bis(2- aminoethyl)thiazole.

J. N,N-bis[4-(4'-nitrophenoxy)benzal]-2-(2-aminomethylphenyl)ethylamine, using 2-(2- aminomethylphenyl)ethylamine.

EXAMPLE 18 Following the procedure described in Example 6A using molarequivalent quantities of the appropriatebis[4-(4'-nitrophenoxy)benzal]-diamine and sodium borohydride, thefollowing compounds can beprenitrophenoxy)benzalaminomethyl]cyclopr0pane.

B. l,3-Bis[4-(4'-nitrophenoxy)benzylaminomethyl]- cyclopentane, usingl,3-bis[ 4-( 4 19 C. N,N'-bis(dichloroacetyl)-N,N'-bis[4-(4'-nitrophenoxy )benzyl]-2,6-bis( aminomethyl)pyridine.

I claim: 1. A compound of the formula D. N,N'-bis(dichloroacetyl )-N,N-bis]4-4 nitrophenoxy)benzyl]-2,5-bis(aminomethyl)pyridine.

E. N,N'-bis( dichloroacetyl)-N,N-bis[4-(4nitrophenoxy)benzyl]-3,4-bis(aminomethyl)pyridine.

F. N,N'-bis(dichloroacetyl)-N,N'-bis[4-(4'-nitrophenoxy)benzyl]-2,5-bis(aminomethyl)furan.

G. N,N'-bis(dichloroacetyl)-N,N-bis[4-(4- nitrophenoxy)benzyl]-l,4-bis(aminomethyl)-2,5- dimethylbenzene.

H. N,N-bis(dichloroacetyl)-N,N'-bis[4-(4- nitrophenoxy)benzyl]-l,3-bis(aminomethyl)benzene.

I. N,N'-bis( dichloroacetyl)-N,N-bis[4-(4 nitrophenoxy)benzyl ]-2,4-bis( 2-aminoethyl )thiazole.

J N,N'-bis(dichloroacetyl)-N,N '-bis[4-(4- nitrophenoxy)benzyl]-2-(2-aminomethylphenyl)ethylamine.

wherein Y is alkylene having from two to ten carbon atoms and having itsconnecting linkages on different carbon atoms or said alkyleneinterrupted by O, S, NH, N(lower-alkyl), cycloalkylene having from threeto six ring carbon atoms, phenylene or phenylene having to claim 1.

1. A COMPOUND OF THE FORMULA
 2. N,N''-bis4-(4''-nitrophenoxy)benzal!-1,8-octanediamine according to claim 3.N,N''-bis 4-(4''-nitrophenoxy)benzal!-1,6-hexanediamine according toclaim
 4. N,N''-bis 4-(4''-nitrophenoxy)benzal!-1,2-ethanediamineaccording to claim
 5. N,N''-bis4-(4''-nitrophenoxy)benzal!-1,3-propanediamine according to 6.Trans-N,N''-bis 4-(4''-nitrophenoxy)benzalaminomethyl!-1,4-cyclohexane7. 1,4-Bis 2-4-(4''-nitrophenoxy)benzalamino!ethyl-2,3,5,6-tetramethylbenzeneaccording to claim 1.